Anti Hypertensive Medications

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Atenolol

Back 1

Selective Beta 1 blocker
Use: Angina, htn, post MI cardioprotection

MOA: Competitively blocks B1 receptors

Less lipophilic; fewer CNS SE

ADR: Bronchoconstriction with higher does because of B2 receptor blockade

Additive hypotensive effect with nitrates and antihypertensive drugs; additive bradycardia with digoxin; decreases the effects of dopamine and dobutamine; unopposed alpha adrenergic receptor stimulation with epinephrine and related drugs

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What drugs do you use for High Risk Angina Pectoris?

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Beta blockers, Calcium Channel Blockers

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Drugs used in Diabetes

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Diuretics, ACEI, ARB

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Drugs used in Recurrent Stroke

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ACEI

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Drugs used in Heart Failure

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Diuretics, Beta blockers, ACE inhibitors, ARB

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Drugs used in Previous MI

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Beta Blockers, ACEI

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Chronic Renal Disease

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ACEI, ARB

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Centrally Acting Sympatholytics

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Clonidine
Guanabenz
Guanfacine
Alpha-Methyldopa

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MOA of Centrally Acting Sympatholytics

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Act within CNS at the vasomotor center

Stimulate most likely alpha2 receptors in the VMC

Decrease sympathetic outflow

Inhibit peripheral release of NE via the decreased VMC sympathetic outflow

Leave baroreceptor and parasympathetic activity predominating

LEads to reduction in peripheral resistance, reduction in heartrate, reduction in force of contraction, and reduction in CO which reduces BP

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Common Side Effects of centrally acting alpha 2 agonists

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Sedation
Nightmares
Impaired Concentration
Depression
Extrapyramidal signs (parkinson like symptoms)
Lactation in Men (Reduced Dopamine levels lead to Increased Prolactin)

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Selective alpha 1

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Prazosin (1st line)
Terazosin
Doxazosin

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Clonidine

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alpha 2 agonist

Transdermal patch is associated with less sedation, but icommonly causes skin reaction

NOt to be used in depressed patients

TCA block the antihypertensive effects of clonidine since they block alpha 2 receptors

Normal oral therapy doesn't lead to HTN, but overdoses do

Withdrawal of clonidine should be gradual to avoid rebound HTN

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Nonselective Alpha Blocker side effects

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Tachycardia (alpha1 and 2 receptors are taken, so the NE/Epinephrine binds to the B1 receptors increasing heart rate)

Tolerance

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Prazosin

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T1/2 of 3-4 hrs due to first pass effect

First dose effect- syncopy and hypotension

First dose should be small and given at bedtime

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Terazosin

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First dose effect consisting of hypotension and possibly syncope

has a longer t1/2 due to less first pass effect so once daily dosing is possible (5-20 mg)

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Doxazosin

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Duration of action is sufficient for once daily dosing at 1 mg

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What do Beta blockers do?

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Decrease heart rate
Decrease force of contraction
Decrease CO
Initial increase in TPR via nonselective blockade of B2 receptors

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Mechanism of vasodilation by Nebivolol

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Activated PLC forms IP3 and DAG

IP3 is released and it binds to the receptors in the ER and releases Calcium

Calcium comes out and activates NOS

NOS takes L-Arginine and forms NO

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Beta blockers basic info

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Resting bradycardia and reduction in heart rate during exercise are indications of blocking efficacy

Beta blockers with ISA produce less resting bradycardia, but still block exercise induced increase in HR

Most important SE occur in patients with reduced myocardial reserve, asthma, peripheral vascular disease, diabetes

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Beta contributes to atherogenesis by following mechanisms

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Increase plasma triglycerides
Increase LDL
Decrease HDL

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Beta blockers contraindications

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Sinus bradycardia
Cardiogenic shock
overt cardiac failure
Greter than first degree heart block; prolonged QT interval

Bronchial asthma, including severe COPD

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Beta blockers with ISA

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Produce less receptor upregulation and less receptor supersensitivity

Produce less resting bradycardia, but they still block sympathetic activity

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Propranolol

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First successfully marketed B blocker

b1 5 > B2

Large first pass effect

T1/2 = 3-5 hr

Some CNS effects (weird dreams)

First used as antiarrhythmic event

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Metoprolol

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B1 80 > B2
T1/2 = 3-5 hr
Fewer SE
Decreases Renin release

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Nadolol

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Nonselective B1 and B2 blocker
Not readily metabolized
T1/2 = 14-24 hr
Once daily dosing is possible
No significant CNS effect

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Timolol

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Nonselective B1 and B2 blocker
Lacks local anesthetic action

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Pindolol

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Nonselective B1 and B2 blocker with ISA

Leads to less beta receptor up regulation and less supersensitivity

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Labetalol

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Nonselective B1 and B2 plus alpha 1 blocker
Beta:Alpha block is 3:1
beta blockade occurs at lower doses
Alpha plus beta treatment is good for the treatment of pheochromocytoma

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Nebivolol

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B1 more than 300 > B2
Dual MOA
Blocking B1 to reduce renin release and probably stimulation of B2/B3 leading to eNO production.

Qd dosing

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Carvedilol

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B1 5 > B2

S(-) isomer or racemic mixture exhibits non selective beta blockade while the R (+) exhibits alpha blockade.

May have similar effects as nebivolol on NO production via stimulation of B2

May scavenge ROS

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Bisoprolol

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B1 125 > B2

B1 selectivity is not absolute so that B2 activity occurs at doses above 20 mg

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Control of Smooth muscle contraction and site of action of CCBs

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Don't directly bind to the receptors. They bind to certain sites around receptors

Ca2+ comes in through the channels. Calmodulin combines with Calcium to form a complex. That calcium calmodulin complex activates MLCK which phoshorylates Myosin light chains to produce phosphorylated Myosin. It works with actin to initiate contraction.

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Muscle selectivity of CCBs

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Skeletal muscle is unaffected by CCB's since the calcium is stored within its sarcoplasmic reticulum and contraction is not dependent on extracellular Calcium concentration

Smooth muscle is dependent upon extracellular calcium, therefore it is inhibited by CCBs

Although vascular smooth muscle is most sensitive, smooth muscle of the GI tract (constipation), uterus and bronchi (bronchoconstriction) are also affected.

Generation of cardiac action potentials, cardiac conduction, and cardiac muscle contraction are dependent upon extracellular calcium. Therefore, CCBs decrease chronotropic (rate reducing), dromotropic (reduction in conduction), and inotropic (strength).

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Common side effects of CCB

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Cardiac depression
cardiac arrest
bradycardia
AV block
CHF

Less serious:

Flushing, ankle edema, dizziness, nausea, constipation, and headache

Gingival hyperplasia --> long term users should visit dentists

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Nifedipine ER

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Has greater smooth muscle selectivity over cardiac.

Lack of cardiac depressant effect leads to greater reflex tachycardia

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Verapamil, SR, ER

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Both smooth and cardiac activity

Has cardiac depressant action producing less tachycardia

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Diltiazem SR and ER

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Has significant nonspecific sympathetic antagonism

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Isradipine

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Approved for HTN only

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Nisoldipine

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Could cause edema

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Clevidipine

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IV

Reduces MAP by decreasing systemic vascular resistance

Onset of effect is 2-4 mins and offset is5-15 min

Does not appear to decrease cardiac repolarization

Rapidly metabolized by hydrolysis of the ester linkage

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Mechanism Vasodilators

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Ca2+ --> NOS activation --> conversion of L Arginine to NO-->Transported to smooth muscle-->activates guanylyl cyclase-->Activates cGMP-->Smooth muscle relaxation

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Vasodilators

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Hydralazine
Nitroprusside
Organonitrates
Minoxidil
Diazoxide
Fenoldopam

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Vasodilators that act via generation or release of NO

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Some vaHydralazine causes synthesis of NO from endogenous sources within the endothelial cell, which in turn acts upon guanylyl cyclase in the adjacent smooth muscle to cause vasodilation

inorganic nitrates as Nitroprusside releases NO directly

Organic nitrates such as Nitroglycerin release NO but require cystein to do so

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Tolerance mechanisms in organonitrates

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Require cysteine to release NO. Eventually cysteine stores run out, so NO can't be released

Vitamin C can prevent tolerance because it is a scavenger

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Vasodilators that act via K+ channel opening

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Cause vasodilation by producing hyperpolarization of the smooth muscle membrane making excitation and contraction less likely to occur

Minoxidil and Diazoxide

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Minoxidil

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Needs to be converted to minoxidil sulfate which causes K+ channel opening

Half life of 4 hrs but hypotensive effects may persist for 24 hours

Produces hypertrichosis

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Diazoxide

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Derivative of thiazide diuretics which lacks diuretic action but produces vasodilation probably as a potassium channel opener

Parenterally administered for hypertensive emergencies

Produces a rapid fall in blood pressure leading to tachycardia and increased cardiac output

Antihypertensive effects are improed by administration of a beta blocker to prevent this reflex

use mini bolus injection- NOT RAPID

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Sodium Nitroprusside

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Given partenterally only

Used for HTN emergencies

Has a very short duration of action allowing titration of blood pressure..It's unstable

Cyanide is generated during metabolism which is sulfated to produce thiocyanate. Cyanaide toxicitiy and death may result from prolonged infusion

Administration of sodium thiosulfate as a sulfur donor facilitates the metabolism of cyanide

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Organoitrate

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Major acute side effects include orthostatic hypotension, tachcardia, and headache

Continuous administration produces tolerance to the blood pressure lowering effects as well as headache

Rebound coronaryvasosmpasm and myocardial infarction may occur during withdrawal of nitrates

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Hydralazine

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Well absorbed but rapidly metabolized by first pass via acetylation. Some pateients are fast acetylators while others are slow

Usual dose is 40-2-- mg/day

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Angiotensin II Functions

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Vasoconstriction
Increase Na/H2O retention cuz of Aldosterone

Inhibits the action of Bradykinin which vasodilates via the secretion of prostaglandins

Increases the release of catecholamines from the renal medulla

Increases the release of growth factors which results in atherogenesis

Increase sympathetic release, Increased ADH, INcreased Thirst

Increases the contractility, hypertrophy of the myocardium

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ACEInhibitors

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Reduced output of sympathetic nervous stimulation

Increased vasodilation of vascular smooth muscles

Decreased retention of sodium and water

Increased levels of bradykinin

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ACE Inhibitors Toxicity

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Severe hypotension can occur in patients exhibiting hypovolemia due to diuretics, salt restriction and GI fluid loss

ARF, hyperkalemia, angioedema and dry cough may occur

Altered sense of taste, allergic skin rashes and drug fever

Drug interactions can occur with K= supplements and potassium sparing diuretics to produce hyperkalemia

NSAIDS impair the antihypertensive effect of ACE inhibitors possibly by blocking the bradykinin mediated vasodilation, which is thought to be prostaglandin mediated

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MEchanism by which ACEIs cause renal failure in patients with bilateral renal artery stenosis

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Stenosis --> Decreased efferent arteriolar pressure-->leads to Decreased GFR

In response to decreased efferent arteriolar pressure-->AII is released and it increases efferent arteriolar pressure which increases GFR...ACEI blocks this process

Front 55

Captopril

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First nonpeptide ACEI
NO agonist action
NOT a prodrug
May produce bone marrow depression which may be fatal
Has SH group which is attributed to some side effects

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Enalapril

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Prodrug metabolized to enalaprilat
NO SH group and is less likely to produce skin reactions, rash, and leukopenia

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Lisinopril

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Lysine derivative of enalaprilat

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Benazepril, Fosinopril and Ramipril

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They lack the sulfhydryl group

All prodrugs like nalapril that are converted to active forms in the gut and liver

Benazepril and ramipril are excreted mainly by the kidney while fosinopril can be metabolized by liver or kidney and excreted in bile or urine, respectively. Dosage adjustment with fosinopril is not necessary when renal function is impaired

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AT1 receptor antagonists

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AT1 receptors are located on vascular smooth muscle and adrenal gland

Losartan Valsartan Candesartan Irbesartan Telmisartan

Alzilsaran is the newest
Mechanisms of antagonism is competitive antagonism

However, slow dissociation of the antagonist may produce doese effect curves resembling irreversible antagonism

Front 60

Losartan

Back 60

First effective, non peptide AT antagonist

Metabolized to an active metabolite

Has 1000 times greater affinity for the AT1 receptor over AT2

Lacks intrinsic or partial agonist activity and does not inhibit ACE, nor does it block other hormone receptors or ion channels important in CV function

Front 61

Valsartan

Back 61

Non peptide
Orally effective AT1 receptor antagonist with 20K fold selectivity for AT1
Metabolite of valsartan is inactive

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Aliskiren

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Renin Inhbitors

high affinity for renin

half life 24 hrs

Plasma renin concentration increases as a compensatory mechanism but Plasma Renin ACtvity does not increase